Graft loss from chronic rejection, which affects all solid organs to varying degrees, has become the major obstacle to the long-term success of lung transplantation. We have established a large animal model of chronic lung rejection, which reproduces with fidelity and consistency, the pathological lesions seen in human lung transplant recipients suffering from chronic rejection. Based on preliminary data and human studies, we hypothesize that chronic lung rejection is an immunologically mediated process driven by T cell recognition of major and minor histocompatibility antigens. The corollary to this hypothesis is that protocols to downregulate the immune system or to induce immune tolerance will most effectively prevent, interrupt and/or reverse chronic lung rejection. The goal of this proposal is to test this hypothesis and, in doing so, investigate the immunologic mechanisms underlying the process of chronic lung rejection. Using MHC inbred miniature swine, synthetic polymorphic allopeptides, and monoclonal antibodies cross-reactive for swine T cells, we plan to (1) define the immunogenetic requirements of chronic lung allograft rejection and characterize the cellular and humoral mechanisms that mediate this disease, (2) examine the role and mechanisms of indirect allorecognition of donor MHC peptides in the development of chronic lung rejection in miniature swine, and (3) determine the role of costimulatory molecules in the pathogenesis of chronic lung rejection in miniature swine. These studies should lead to a better understanding of the cellular and molecular mechanisms of chronic lung rejection in a clinically relevant experimental model and may ultimately lead to the development of new strategies to prevent or treat this disease.